Exposure to particulate air pollution reduces life expectancy and likely contributes to the increased incidence of asthma, allergy, and pulmonary and cardiovascular disease. Inhalation of particulate matter (PM) causes airway hyperresponsiveness, cellular inflammation, and mucus secretion, which appear to be mediated in large part by activated T cells. When T cells are activated, they initiate a program that promotes survival and initiates rapid proliferation. This switch from a resting state to a highly proliferative state requires substantial alterations in cell metabolism. The current dogma of T cell metabolism is that naive resting T cells rely on mitochondrial metabolism and activated T cells rely on glycolytic metabolism, however the current project will challenge this dogma. In many proliferating cells, glycolysis may be important as a conduit to the pentose phosphate pathway, but it is insufficient to provide the full complement of factors needed for proliferation. Mitochondrial metabolism is needed to produce citrate through the TCA cycle to make lipids for membrane synthesis. Furthermore, it has been shown that mitochondrial ROS are required to promote cell cycle progression. The current proposal will utilize mice that have mitochondrial metabolic genes conditionally deleted in T cells to elucidate the role of mitochondrial metabolism in T cell activation. We will challenge these mice with PM exposure to see if inhibition of mitochondrial metabolism could reduce T cell-mediated inflammation. The results of this study could fundamentally change the current conception of T cell metabolism, as well as provide metabolic and signaling targets that could be subject to control by pharmaceutical agents. PUBLIC HEALTH RELEVANCE: Inhalation of particulate matter (PM) induces T cell-mediated inflammation and correlates with increased incidence of asthma, allergy, and pulmonary and cardiovascular disease. This project will assess the role of mitochondrial metabolism in T cell activation and use PM exposure as a model to determine metabolic requirements of T cell-mediated inflammation. Importantly, this work will define metabolic and signaling pathways that could be modulated by pharmaceutical agents to dampen the T cell response to PM or other benign antigens.